Anionic ring expansion reactions of oxabicyclo[4.2.1]heptenones. An efficient entry into the carbon framework of oxygenated cembranoids

Article abstract of DOI:10.1016/S0040-4020(01)00778-5

Oxabicyclo[2.2.1]heptenones undergo 2-carbon ring expansion reactions when subjected to anionic condensations and Michael acceptors. They also undergo condensation, fragmentation, and elimination reactions in their anionic couplings with aldehydes. As an outgrowth of this interesting chemistry, we have been able to access the carbon skeleton of oxygenated cembranoids by subjecting bis-activated ene-yne 39 to the enolate from oxabicyclo[2.2.1]heptenone 1.

Full text of DOI:10.1016/S0040-4020(01)00778-5

TETRAHEDRON
Pergamon
Tetrahedron 57 42001) 8029±8037
Anionic ring expansion reactions of oxabicyclo[4.2.1]heptenones.
An ef®cient entry into the carbon framework
of oxygenated cembranoids
Qing Xu, Mahika Weeresakare and Jon D. Rainierp
Department of Chemistry, The University of Arizona, Tucson, AZ 85721, USA
Received 9 July 2001; accepted 26 July 2001
AbstractÐOxabicyclo[2.2.1]heptenones undergo 2-carbon ring expansion reactions when subjected to anionic condensations and Michael
acceptors. They also undergo condensation, fragmentation, and elimination reactions in their anionic couplings with aldehydes. As an
outgrowth of this interesting chemistry, we have been able to access the carbon skeleton of oxygenated cembranoids by subjecting bis-
activated ene-yne 39 to the enolate from oxabicyclo[2.2.1]heptenone 1. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
2.1. The synthesis of oxabicyclo[2.2.1]heptenone 1
The oxygenated cembranoid family of natural products has
received a signi®cant amount of attention from the synthetic
chemistry community. Undoubtedly, this is due to their
fascinating structural features and their interesting bio-
logical properties. To date, this attention has led to the
total synthesis of several members of this family 4eleuther-
obin,1 eleuthosides A and B,2 sarcodictyin A and B,3
7-deacetoxyalcyonin acetate,4 and sclerophytin A and B5)
along with a number of approaches to their synthesis.6
The plan outlined in Scheme 1 required the synthesis of
oxabicyclo[2.2.1]heptenone 1. Dithioketal precursors to 1
and the corresponding 3,6-dihydro derivative 14 4Table 2)
came from the condensation of bromopropiolate 8 with
2-methoxy-5-methyl furan or furan followed by dithioketal
formation using anionic conditions analogous to conditions
used by Leroy for the formation of the cyclic dithioketal
derivative of 13 4Table 1).10
Our interest in the chemical synthesis of the oxygenated
cembranoids directed our attention to the notion that their
carbon skeleton could be assembled through the intra-
molecular cyclization and fragmentation sequence depicted
in Scheme 1 43!5).7±9
Leroy had been unsuccessful in his attempts to hydrolyze
the cyclic dithiane analog of 13.11 Notsurprisingly, our
attempts to hydrolyze the cyclic dithiane in the more sensi-
tive 11 were equally unsuccessful. Fortunately, we were
In an attempt to implement this plan, we discovered an
interesting anionic coupling and fragmentation reaction of
oxabicyclo[2.2.1]heptenones.7a This result along with others
that came from subsequent experiments,7b directed our
attention to a modi®ed approach to the eleuthosides.
Described herein is a full accountof our experimenst in
these areas including a single ¯ask entry into the carbon
skeleton of the oxygenated cembranoids using a tandem
anionic cyclization sequence.
Keywords: oxygenated cembranoid; eleutherobin; ring expansion; fragmen-
tation; heterocycles.
p
Corresponding author. Tel.: 11-520-626-2084; fax: 11-520-621-8407;
e-mail: rainier@u.arizona.edu
Scheme 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020401)00778-5

8030
Q. Xu et al. / Tetrahedron 57 '2001) 8029±8037
Table 1.
Table 3.
Entry
R
Furan
Yield 4%)
Z:Ea
1
2
3
4
Ph
i-Pr
4CH2)3OBn
CO2Et
17
18
19
20
83
78
68
91
.98:2
.98:2
.98:2
5.4:1
S,S ketal
R
R0
R00
endo:exoa
Yield 4%)
a
1
Ratio determined by H NMR.
11
12
13
OCH3
OCH3
H
CH3
CH3
H
CH2CH2
Et
Et3:1
.98:2
.98:2
89
95
96
to carry out experiments aimed at gaining an understanding
of the reactivity of 15 with aldehydes in an effort to model
its coupling with 2. To our surprise, the addition of benz-
aldehyde to 15 at0 8C resulted in the formation of dihydro-
furan 17 in 83% yield 4Table 3).13 Interestingly, the
coupling of 2 with benzaldehyde results in a cascade
sequence that mechanistically incorporates several chemical
processes including condensation, fragmentation, and elimi-
nation. As this represented what could be an interesting
entry into the synthesis of substituted furans we decided
to explore its scope. We were pleased to ®nd that the reac-
tion was general. In addition to benzaldehyde, isobutyr-
aldehyde, ethyl glyoxylate, and 4-benzyloxybutanal also
underwent the condensation and fragmentation sequence
to give furans 18, 19, and 20 in 78, 68 and 92% yield,
respectively. Each of the products existed either predomi-
nantly or exclusively as its Z-ole®n isomer.
a
Ratio determined by 1H NMR.
Table 2.
S,S, Ketal
R0
R
Ketone
Yield 4%)
endo:exoa
b
11
12
13
CH3
CH3
H
OCH3
OCH3
H
1
1
14
±
±
44
55
.98:2
2:1c
a
Ratio determined by 1H NMR.
b
Attempted hydrolysis under all conditions resulted in the decomposition
of the oxabicyclo[2.2.1]heptenone ring.
Partial epimerization took place during thioketal hydrolysis.
c
able to overcome these problems by turning to the corre-
sponding acyclic dithiane 12. Hydrolysis using Hg4ClO4)2
provided a 44% yield of b-ketoester 1. In a similar
fashion, we were able to generate 14 in 55% yield from
the hydrolysis of 13.
2.2. Anionic condensations of 1
Since the success in the anionic coupling of 1 with 2
4Scheme 1) was dependent upon our ability to overcome a
potentially facile b-fragmentation reaction of the enolate
from 1 4i.e. 15, Eq. 41)),12 we carried outexperimenst
aimed at determining the stability of 15. We were pleased
to ®nd that 15 was stable at 08C as witnessed by its trapping
with MeI. When 15 was allowed to warm to rt, however,
products resulting from the decomposition of the bicyclic
ring system were isolated.
Scheme 2.
Table 4.
Furan
R
Yield 4%)
Z:Ea
24
25
Ph
i-Pr
56
45
1:3
2:1
ꢀ1†
a
1
Ratio determined by H NMR.
Having de®ned its temperature stability pro®le, we decided

Q. Xu et al. / Tetrahedron 57 '2001) 8029±8037
8031
Table 5.
Entry
Michael acceptor
Product
R
R0
Yield 4%)
a:b
1
2
3
4
5
Methyl acrylate
26
28
29
30
31
H
CO2CH3
H
H
H
CO2CH3
CO2CH3
C4O)CH3
C4O)4CH2)3CHCH2
CH3
70
60
60
70
2.5:1
±
2.5:1
2.5:1
±
a
Dimethyl fumarate
Methylvinyl ketone
4-Pentenylvinyl ketone
Methacrylate
b
±
a
Mix of three diastereomers at C-3 and C-4.
Reaction led to the recovery of starting material.
b
Our working hypothesis for the condensation, fragmentation
sequence is depicted in Scheme 2. Following the initial
coupling reaction, oxyanionic cyclization gives oxetane
22. Fragmentation of the bicyclic ring system with con-
comitant elimination of the ester leads to the formation
of the corresponding ole®n and 23. Workup of the reac-
tion with methyl iodide gives the corresponding methyl
ester.
followed by methyl acrylate 4Eq. 42)). The products from
this reaction proved to be the ring expanded bicycles 26 and
27 as a 2.5:1 mixture of readily separable diastereomers.
When combined with our aldehyde condensation studies,
this experiment demonstrated that four-membered ring
formation is facile in oxabicyclo[2.2.1]heptenone conden-
sations.
While we do not currently have an explanation for the
predominance of the Z-ole®n from these coupling reactions,
we do know that bridgehead substitution is important in
the selectivity. That is, in contrast to the condensation
chemistry of 1, the condensation of 2,5-unsubstituted oxa-
bicyclo[2.2.1]heptenone 14 with benzaldehyde and iso-
butyraldehyde led to mixtures of the E- and Z-alkenes of
24 and 25, respectively 4Table 4).14
ꢀ2†
As presented in Table 5, other Michael acceptors also under-
went the two-carbon ring expansion cascade with 1. Thus,
dimethyl fumarate, methylvinyl ketone, and 4-pentenyl-
vinyl ketone gave ring expanded products 28, 29, and 30,
respectively.
2.3. Two- and four-carbon ring expansions of oxa-
bicyclo[2.2.1]heptenones
Having discovered the interesting reactions of aldehydes
with oxabicyclo[2.2.1]heptenones 1 and 14, we initiated a
program to examine the hypothesis presented in Scheme 2.
If 1 could be induced to undergo a Michael addition onto an
activated alkene and if the aldehyde mechanism were opera-
tive, the Michael adduct would undergo cyclization onto the
pendant ketone to generate two-carbon ring expanded
products. With this in mind, 1 was subjected to NaH
Not surprisingly, proton transfer from the newly formed
b-ketoester 41,3-diketone) to the anion from the fragmen-
tation of the [2.2.1] ring systems occurred in the course of
the reaction with methyl acrylate 4Scheme 3). As proof of
this, we were able to incorporate deuterium at C-2 when the
reaction was quenched with D2O.
Table 6.
Entry
Alkyne
R
R0
Yield 4%)
92
36:37
1
2
MeO2C±u±CO2Me
Et 2C±u±OH
CO2Me
H
Me
Et44
1:0
a
1:1.3
a
37 was isolated as a 1:1 mixture of C-2 diastereomers.
Scheme 3.

8032
Q. Xu et al. / Tetrahedron 57 '2001) 8029±8037
Table 7.
Having demonstrated the two-carbon ring expansions of 1,
we turned our attention back to the synthesis of oxygenated
cembranoids. We became intrigued with the possibility of
generating their oxygen-bridged 10-membered ring through
an anionic two-carbon ring expansion reaction of oxa-
bicyclo[4.2.1]heptenone 26 with activated alkynes using
Proctor's protocol.15 The treatment of 26 with NaH
followed by DMAD resulted in the formation of oxygen
bridged cyclodecadiene 36 in 92% yield 4Table 6). Unfortu-
nately, other activated alkynes were not as reactive as
DMAD. For example, when 26 was exposed to NaH
followed by ethyl propiolate we isolated a 1:1.3 mixture
of ring expanded and Michael adducts 36 and 37, respec-
tively. As has been discussed by Proctor,15 the reaction
leading to 36 most likely proceeds through the formation
of a cyclobutene intermediate followed by a subsequent
fragmentation reaction.
Conditions
R
Yield 4%)
40:47
NaH, DMF, 258C, 12 h
NaH, DMF, 508C, 12 h
KH, DMF, 258C, 1 h;
Ac2O, DMAP
H
H
Ac
80
40
50
1:1
1:0
1:0
Interestingly, the relative stereochemistry at the ethyl ester
bearing stereocenter was important in the two-carbon ring
expansion reaction of oxabicyclo[4.2.1]nonenes with
activated alkynes. When 27 was exposed to NaH, DMAD,
and THF we isolated 38 in low yield 4Eq. 43)). The
majority of the reaction mixture consisted of intractable
material.
ated cembranoids from relatively simple substrates.
ꢀ3†
ꢀ5†
With these goals in mind, we synthesized ene-yne 39 from
t-butyl imine 41 4Scheme 4). The anionic coupling of 41
with the TBDPS ether of bromopropanol gave 4216 after
vinyl magnesium bromide addition, MOM ether formation,
and hydrolysis of the TBDPS group. Oxidation of the result-
ing alcohol was followed by alkyne formation using the
Corey±Fuchs protocol to give 43 after trapping of the
alkynyl anion with methylchloroformate.17 Methanolysis
of the MOM ether and PCC oxidation gave ene-yne
coupling precursor 39.
By taking advantage of the proton transfer that was
observed in the initial two-carbon ring expansion reaction
4Scheme 3), we were able to carry out a single ¯ask, four-
carbon ring expansion of 1. Thatis, by exposing 1 to NaH
and DMF followed by methyl acrylate and then DMAD
in THF we were able to isolate oxygen bridged cyclo-
decatriene 36 in 42% overall yield 4Eq. 44)).
ꢀ4†
2.4. Tandem anionic ring expansion reactions
Scheme 4. 4a) LDA; BrCH2CH2CH2OTBDPS 490%); 4b) BrMgCHvCH2
465%); 4c) MOMCl, 4i-Pr)2NEt485%); 4d) TBAF 4100%); 4e) 4i) 4COCl)
DMSO, NEt3; 4ii) PPh3, CBr4 42 steps, 65%); 4f) BuLi 42 equiv.); ClCO2Me
487%); 4g) HCl, CH3OH 480%); 4h) PCC 479%).
2
Having demonstrated the formation of 36 from 1 and two
sequential two-carbon ring expansion reactions, we became
curious about the possibility of using a similar protocol to
generate the oxygenated cembranoid carbon skeleton. That
is, we believed that 40 mightcome from hte anionic
coupling of 1 with a molecule containing two Michael
acceptors linked to one another through an alkyl chain
4e.g. 39). If this endeavor was successful, we would be in
a position to ef®ciently generate a wide variety of oxygen-
2.4.1. Stepwise generation of oxygenated cembranoid
skeleton 40. In an effort to determine the feasibility of the
sequential two-carbon ring expansion for the synthesis of
40,18 we decided to initially proceed in a stepwise fashion
via the formation of oxabicyclo[4.2.1]nonene 45 4Eq. 46)).

Q. Xu et al. / Tetrahedron 57 '2001) 8029±8037
8033
With this in mind, the alkyne in 39 was masked as the
corresponding Co24CO)6 complex 4e.g. 44).19 The anionic
coupling of 44 with 1 gave a 55% yield of readily separable
diastereomeric oxabicyclo[4.2.1]nonenes 45 and 46.
C-4 ester is directing the attack, approach from the a-face
does not appear to be productive.
2.4.2. Single ¯ask entry into the oxygenated cembranoid
skeleton 40. Having established that 1 could be transformed
into the corresponding tricycle in a stepwise fashion, we
investigated the single step conversion of 1 into the oxy-
genated cembranoid skeleton through its reaction with 39
4Eq. 47)).24 In the event, we isolated 50 in 20% yield by
subjecting 1 to 39 and KH at rt followed by in situ acylation
of the doubly ring expanded enolate.25 The main by-product
from the reaction 422% yield) was spirofused substrate 47 as
a mixture of diastereomers. Although formed in a modest
yield, the conversion of 1 into 50 represents an impressive
combination of the coupling and fragmentation of six C±C
bonds in a single ¯ask and an almost direct entry into the
oxygenated cembranoid skeleton.
ꢀ6†
Following oxidative decomplexation of cobalt from the
alkyne using trimethylamine-N-oxide 4TMANO),20 each
of the C-4 diastereomers was subjected individually to the
anionic two-carbon ring expansion reaction. When 45 was
treated with NaH at rt for 12 h, we isolated a 40% yield of
the desired ring expanded product 40 along with a 40% yield
of spirofused product 47 as a single diastereomer 4Table
7).21 When the reaction was carried out at 508C for 12 h, a
ꢀ7†
In conclusion, we have demonstrated that oxabicyclo-
[2.2.1]heptenones undergo anionic coupling and fragmen-
tation sequences with aldehydes and Michael acceptors.
These reactions lead to the synthesis of substituted dihydro-
furans as well as ring expanded products including the
carbon skeleton of oxygenated cembranoids.
40% yield of 40 was isolated. Under these conditions,
formation of 47 was notobserved.
22
We also examined
the effectiveness of KH as the base in the 45!40 con-
version. When 45 was subjected to KH at 08C and allowed
to warm to rt over 1 h we isolated a 50% yield of the enol
acetate of 40 after acylation of the crude reaction mixture.23
As in the experiment using NaH at elevated temperatures,
we did notisolaet 47 using these conditions.22
3. Experimental
3.1. General
NMR spectra were recorded on either a Bruker EM-600,
Bruker EM-500, Bruker AM-250, or a Varian 300 spectro-
meter. Chemical shifts were reported in d, parts per million
4ppm), relative to chloroform 4dˆ7.24 ppm) as an internal
standard. Coupling constants, J, were reported in Hertz 4Hz)
and refer to apparent peak multiplicities and not true
coupling constants. Mass spectra were recorded at the
Mass Spectrometry Facility at the Department of Chemistry
of the University of Arizona on a Jeol HX-110A and are
reported as % relative intensity to the molecular base peak.
IR spectra were recorded on a Nicolet Impact 410.
Ether, THF, hexanes, benzene, and toluene were distilled
from sodium/benzophenone. CH2Cl2, CHCl3, TMEDA,
4i-Pr)2NEt, Et3N, and Et2NH were distilled from CaH2. All
other reagents were used without puri®cation. Unless other-
wise stated, all reactions were run under an atmosphere of
argon in ¯ame-dried glassware. Concentration refers to
removal of solventunder reduced pressure 4house vacuum
atca. 20 mmHg) wiht a Bu Èchi Rotavapor. Characterization
data for compounds 6±14 ,17, 18, 24, 30, 36, and 37 have
been reported elsewhere.7,10
Interestingly, in an analogous fashion to what we had
observed in the intermolecular ring expansion reaction of
27, C4 b-diastereomer 48 decomposed to unrecognizable
products when exposed to the anionic fragmentation con-
ditions 4Scheme 5). The reason for the divergent reactivity
pro®les of uncomplexed 45 and 48 is unclear atthe present
time but may be due to the facial approach of the activated
alkyne onto the intermediate enolate. If this is true and the
3.1.1. Preparation of dihydrofuran 19. To a slurry of NaH
42.4 mg, 0.097 mmol) and DMF 40.3 mL) at0 8C was added
Scheme 5.

8034
Q. Xu et al. / Tetrahedron 57 '2001) 8029±8037
a solution of 1 422 mg, 0.097 mmol) and DMF 40.3 mL).
After stirring for 1 h, 4-benzyloxybutanal 487 mg, 0.486
mmol) was added slowly. After stirring for an additional
1 h, MeI 40.3 mL, 0.5 mmol) was added and the reaction
mixture was stirred for another 1 h. After quenching with
NaHCO3 44aq, sat) 8 mL), the mixture was extracted with
ethyl acetate 43£1 5 mL), dried 4Na2SO4) and concentrated.
Flash chromatography 46:1 hexane/ethyl acetate) provided
27 mg 468%) of furan 19 as a colorless oil.: 1H NMR
4600 MHz, CDCl3) d 7.34 4m, 5H), 7.26 4m, 1H), 6.61 4t,
Jˆ7.7 Hz, 1H), 6.25 4d, Jˆ6.0 Hz, 1H), 6.08 4d, Jˆ6.0 Hz,
1H), 4.49 4s, 2H), 4.24 4m, 2H), 3.71 4s, 3H), 3.48 4t, Jˆ
6.5 Hz, 2H), 3.24 4s, 3H), 2.39 4m, 2H), 1.77 4m, 2H), 1.65
4s, 3H), 1.28 4t, Jˆ7.1 Hz, 3H); 13C NMR 4600 MHz,
CDCl3) d); 13C NMR 4600 MHz, CDCl3) d 172.3, 167.0,
140.3, 138.7, 133.1, 132.7, 130.9, 128.4, 127.7, 127.5,
123.4, 113.6, 89.6, 73.0, 69.8, 60.6, 52.1, 50.4, 29.3, 26.2,
phase was extracted with ether 4200 mL£3). The organic
extracts were dried 4MgSO4) and concentrated. Flash
chromatography 4hexanes/ethyl acetate 5:1) gave 4.0 g
474%) of 4,4-dimethyl-7-t-butyldiphenylsilanyloxy-1-hep-
1
tene-3-ol as a colorless oil. H NMR 4600 MHz, CDCl3):
d 4ppm) 7.65 4dd, Jˆ7.8, 1.2 Hz, 4H), 7.42±7.34 4m, 6H),
5.90 4ddd, Jˆ17.3, 10.5, 6.8 Hz, 1H), 5.20 4ddd, Jˆ17.2,
1.2, 1.2 Hz, 1H), 5.15 4ddd, Jˆ10.4, 1.2, 1.2 Hz, 1H), 3.78
4d, Jˆ6.6 Hz, 1H), 3.62 4t, Jˆ6.6 Hz, 2H), 1.58±1.48 4m,
2H), 1.33 4ddd, Jˆ13.2, 6.0, 2.4 Hz, 1H), 1.23 4ddd, Jˆ16.2,
12.0, 6.0 Hz, 1H), 1.04 4s, 9H), 0.86 4s, 3H), 0.82 4s, 3H).
13C NMR 4150 MHz, CDCl3): d 4ppm) 137.9, 135.6, 134.1,
129.5, 127.6, 127.5, 116.4, 79.9, 64.7, 36.9, 34.6, 27.0, 26.9,
22.8, 22.7, 19.2; IR 4CCl4) 2969, 1548 cm21
.
3.1.4. Preparation of 4,4-dimethyl-5-methoxymethoxy-6-
heptene-1-ol 042). To a solution of 4,4-dimethyl-7-t-butyl-
diphenylsilanyloxy-1-heptene-3-ol 44.0 g, 10.1 mmol) and
CH2Cl2 410 mL) was added MOMCl 41.62 g, 20.2 mmol)
followed by a solution of i-Pr2NEt43.52 mL, 20.2 mmol)
and CH2Cl2 410 mL). After stirring for 12 h, the mixture was
quenched with NaHCO3 44sat, aq.) 20 mL). The aqueous
phase was extracted with ether 4200 mL£3), dried
4MgSO4), and concentrated to provide the MOM ether.
The MOM ether was taken on to the formation of 42 without
further puri®cation.
25.0, 14.3; IR 4CCl4) 2999, 2851, 1785, 1746, 1696 cm21
;
HRMS 4FAB) calcd for C23H30O7 4M1Cs1) 551.1042,
found 551.1050.
3.1.2. Preparation of dihydrofuran 20. To a slurry of NaH
42.0 mg, 0.084 mmol) and DMF 40.3 mL) at0 8C was added
a solution of 1 422 mg, 0.097 mmol) and DMF 40.3 mL).
After stirring for 1 h, ethyl glyoxylate 443 mg, 0.42 mmol)
was then added slowly to the reaction mixture. After an
additional 1 h, MeI 40.3 mL, 0.5 mmol) was added and
the reaction mixture was stirred for another 1.5 h. After
quenching with NaHCO3 4aq, sat. 8 mL), the mixture was
extracted with ethyl acetate 43£15 mL), dried 4Na2SO4), and
concentrated. Flash chromatography 43:1 hexanes/ethyl
acetate) provided 30 mg 491%) of furan 20 as a 5.4:1
To a solution of the crude MOM ether from above and THF
430 mL), was added TBAF 417 mL of a 1 M solution in
THF, 17.2 mmol). After stirring for 2.5 h, the reaction was
quenched through the addition of H2O 450 mL). The
aqueous phase was extracted with ethyl acetate 43£
200 mL). The organic extracts were dried and concentrated.
Flash chromatography 4hexanes/ethyl acetate 3:2) gave
1
mixture of ole®ns as a colorless oil. Z-isomer: H NMR
4600 MHz, CDCl3) d 6.68 4s, 1H), 6.15 4d, Jˆ5.8 Hz,
1
1H), 6.09 4d, Jˆ5.8 Hz, 1H), 4.30 4dq, Jˆ10.8, 7.1 Hz,
1.8 g 485%) of 42 as a colorless oil. H NMR 4600 MHz,
²
²
2H), 4.18 4dq, Jˆ10.8, 7.1 Hz, 2H), 3.75 4s, 3H),3.31 4s,
3H), 1.67 4s, 3H), 1.32 4t, Jˆ7.1 Hz, 3H), 1.28 4t, Jˆ7.1 Hz,
3H); 13C NMR 4600 MHz, CDCl3) d 171.6, 166.3, 164.9,
147.2, 133.9, 129.2, 123.4, 112.6, 90.5, 61.5, 60.9, 52.5,
50.7, 24.8, 14.0, 13.8; IR 4CCl4) 2981, 1752, 1739,
1023 cm21; HRMS 4FAB) calcd for C16H22O8 4M1H1)
343.1393, found 343.1396.
CDCl3): d 4ppm) 5.64 4ddd, Jˆ17.4, 10.2, 8.4 Hz, 1H), 5.22
4dd, Jˆ10.2, 1.8 Hz, 1H), 5.13 4dd, Jˆ17.4, 1.2 Hz, 1H),
4.61 4d, Jˆ8.1 Hz, 1H), 4.42 4d, Jˆ8.1 Hz, 1H), 3.63 4d, Jˆ
8.4 Hz, 1H), 3.54 4t, Jˆ6.6 Hz, 2H), 3.30 4s, 3H), 2.20 4bs,
1H), 1.56±1.45 4m, 2H), 1.34 4dt, Jˆ13.2, 4.8 Hz, 1H), 1.22
4ddd, Jˆ12.6, 12.6, 4.8 Hz, 1H), 0.85 4s, 3H), 0.82 4s, 3H);
13C NMR 4150 MHz, CDCl3): d 4ppm) 134.9, 119.1, 93.8,
84.3, 63.6, 55.6, 36.4, 34.5, 26.9, 23.3, 23.2; IR 4CCl4) 3376,
2944, 2888, 1036 cm21. HRMS calcd for C11H23O3 4M1H)
203.1647, found 203.1644.
Z con®guration of the major isomer was con®rmed by the
3
vicinal coupling constant J4CO,H) 11.1 Hz.
E-isomer: H NMR 4600 MHz, CDCl3) d 6.70 4s, 1H), 6.26
4d, Jˆ5.8 Hz, 1H), 6.21 4d, Jˆ5.8 Hz, 1H), 4.30 4dq, Jˆ
3.1.5. Preparation of 4,4-dimethyl-5-methoxymethoxy-6-
heptenal. To a solution of oxalyl chloride 40.87 mL,
9.95 mmol) and CH2Cl2 45 mL) at 2608C was added a solu-
tion of DMSO 40.94 mL, 13.3 mmol) and CH2Cl2 45 mL)
dropwise. After the resulting solution had stirred for 10 min,
a solution of 42 41.34 g, 6.63 mmol) and CH2Cl2 410 mL)
was added. The mixture was stirred for 10 min and a solu-
tion of NEt3 43.71 mL, 26.5 mmol) and CH2Cl2 410 mL) was
added. After warming to rt, the reaction mixture was stirred
for 1 h and then quenched with NH4Cl 44sat, aq.) 30 mL).
The aqueous phase was extracted with ether 4100£3 mL),
dried 4Na2SO4), and concentrated. Flash chromatography
4hexanes/ethyl acetate 3:1) gave 1.30 g 497%) of 4,4-
dimethyl-5-methoxymethoxy-6-heptenal as a colorless oil.
1H NMR 4250 MHz, CDCl3) d 4ppm) 9.75 4t, Jˆ1.8 Hz,
1H), 5.66 4ddd, Jˆ17.0, 10.4, 8.3 Hz, 1H), 5.28 4ddd, Jˆ
10.0, 1.9, 0.5 Hz, 1H), 5.17 4ddd, Jˆ17.2, 1.8, 0.6 Hz, 1H),
²
²
10.8, 7.1 Hz, 2H), 4.18 4dq, Jˆ10.8, 7.1 Hz, 2H) , 3.73 4s,
3H), 3.27 4s, 3H), 1.59 4s, 3H), 1.32 4t, Jˆ7.1 Hz, 3H), 1.311
4t, Jˆ7.1 Hz, 3H); 13C NMR 4600 MHz, CDCl3) d 171.3,
166.0, 165.0, 138.2, 135.1, 129.6, 129.1, 112.4, 90.1, 61.3,
61.0, 52.2, 50.5, 24.5, 14.0, 13.8.
3.1.3. Preparation of 4,4-dimethyl-7-t-butyldiphenyl-
silanyloxy-1-heptene-3-ol. To a solution of vinylmag-
nesium bromide 41 M solution in THF, 20.3 mmol) at 08C,
was added a solution of 5-t-butyldiphenylsilanyloxy-2,2-
dimethylpentanal 45.0 g, 13.5 mmol) and THF 415 mL)
dropwise over 1 h. After stirring for 0.5 h, the mixture
was quenched with NH4Cl 44sat, aq.) 30 mL). The aqueous
²
Z multiplet overlapped with E.

Q. Xu et al. / Tetrahedron 57 '2001) 8029±8037
8035
4.64 4d, Jˆ6.9 Hz, 1H), 4.45 4d, Jˆ6.7 Hz, 1H), 3.64 4d, Jˆ
8.3 Hz, 1H), 3.34 4s, 3H), 2.48±2.38 4m, 2H), 1.71 4ddd, Jˆ
13.9, 10.1, 6.2 Hz, 1H), 1.54 4ddd, Jˆ13.9, 10.5, 6.1 Hz, 1H),
0.88 4s, 3H), 0.86 4s, 3H); 13C NMR 462.5 MHz, CDCl3) d
4ppm) 202.9, 134.6, 119.7, 93.8, 84.1, 55.8, 39.0, 36.3, 30.4,
4ppm) 5.84 4ddd, Jˆ16.7, 10.4, 6.8 Hz, 1H), 5.21 4d, Jˆ
16.8 Hz, 1H), 5.17 4d, Jˆ10.2 Hz, 1H), 3.72 4d, Jˆ6.5 Hz,
1H), 3.68 4s, 3H), 2.33 4ddd, Jˆ16.8, 10.2, 6.0 Hz, 1H), 2.30
4ddd, Jˆ16.8, 10.2, 6.0 Hz, 1H), 1.69 4ddd, Jˆ13.8, 10.2,
6.6 Hz, 1H), 1.56 4d, Jˆ3.6 Hz, 1H), 1.53 4ddd, Jˆ13.8,
10.2, 6.2 Hz, 1H), 4m, 1H), 0.82 4s, 6H); 13C NMR
4150 MHz, CDCl3) d 4ppm) 154.2, 137.4, 116.9, 90.5,
79.4, 72.5, 52.4, 37.0, 36.4, 22.6, 22.3, 13.7; IR 4CCl4)
3537, 2963, 2882, 2246, 1721 cm21; HRMS calcd for
C12H19O3 4M1H) 211.1339, found 211.1334.
23.3, 23.2; IR 4CCl4) 2956, 2888, 1709, 1042 cm21
.
3.1.6. Preparation of 3-methoxymethoxy-4,4-dimethyl-
8,8-dibromo-1,7-octadiene. To a solution of CBr4 44.0 g,
12.0 mmol), PPh3 46.3 g, 24.0 mmol), and CH2Cl2 420 mL)
at0 8C was added a solution of 4,4-dimethyl-5-methoxy-
methoxy-6-heptenal 41.2 g, 6.0 mmol) and CH2Cl2 420 mL)
over 0.5 h. The reaction mixture was diluted with hexanes
4160 mL), ®ltered, and concentrated. Flash chromatography
4hexanes/ethyl acetate 20:1) gave 1.60 g 475%) of 3-meth-
oxymethoxy-4,4-dimethyl-8,8-dibromo-1,7-octadiene as a
3.1.9. Preparation of methyl 6,6-dimethyl-7-oxo-8-
nonene-2-ynoate 039). To a solution of methyl 6,6-
dimethyl-7-hydroxy-8-nonene-2-ynoate 41.2 g, 5.71 mmol)
and CH2Cl2 420 mL) was added PCC 42.46 g, 10.4 mmol).
After 3 h, ether 420 mL) was added to the reaction and the
mixture was ®ltered. Concentration and ¯ash chroma-
tography 4hexanes/ethylacetate 3:1) gave 1.0 g 480%) of
1
yellow oil. H NMR 4500 MHz, CDCl3) d 4ppm) 6.33 4t,
Jˆ7.5 Hz, 1H), 5.66 4ddd, Jˆ17.2, 10.3, 8.4 Hz, 1H), 5.26
4dd, Jˆ10.4, 0.5 Hz, 1H), 5.16 4dd, Jˆ17.5, 1.0 Hz, 1H),
4.66 4d, Jˆ6.8 Hz, 1H), 4.47 4d, Jˆ6.8 Hz, 1H), 3.64 4d,
Jˆ8.3 Hz, 1H), 3.36 4s, 3H), 2.10±2.00 4m, 2H), 1.43 4ddd,
Jˆ13.5, 11.0, 5.5 Hz, 1H), 1.31 4ddd, Jˆ13.5, 11.5, 6.0 Hz,
1H), 0.91 4s, 3H), 0.88 4s, 3H); 13C NMR 4125 MHz, CDCl3)
d 4ppm) 139.2, 134.8, 119.5, 93.9, 88.3, 84.1, 55.8, 36.7,
36.4, 27.9, 23.2, 23.0; IR 4CCl4) 2963, 2888, 1481, 1153,
1
39 as a colorless oil. H NMR 4600 MHz, CDCl3) d 4ppm)
6.72 4dd, Jˆ16.8, 10.2 Hz, 1H), 6.30 4dd, Jˆ16.9, 2.1 Hz,
1H), 5.63 4dd, Jˆ10.3, 2.1 Hz, 1H), 3.68 4s, 3H), 2.19 4m,
2H), 1.84 4m, 2H), 1.12 4s, 6H). 13C NMR 4150 MHz,
CDCl3) d 4ppm) 202.5, 154.0, 130.2, 129.2, 89.0, 72.9,
52.4, 45.8, 36.8, 23.6, 14.3; HRMS calcd for C12H17O3
4M1H) 209.1178, found 209.1169.
1042 cm21
.
3.1.10. Preparation of [methyl 6,6-dimethyl-7-oxo-8-
nonene-2-ynoate] dicobalt hexacarbonyl complex 044).
A solution of 39 40.212 g, 1.02 mmol) and ether 41 mL)
was added to a solution of dicobalt octacarbonyl 40.348 g,
1.02 mmol) and ether 46 mL) at rt. After 2 h the mixture was
concentrated. Flash chromatography 4hexanes/ethyl acetate
3.1.7. Preparation of methyl 6,6-dimethyl-7-methoxy-
methoxy-8-nonene-2-ynoate 043). To a solution of 3-meth-
oxymethoxy-4,4-dimethyl-8,8-dibromo-1,7-octadiene 41.49 g,
4.18 mmol) and THF 420 mL) at 2788C was added BuLi
45.58 mL of a 1.5 M solution in hexane, 8.37 mmol).
1
7:1) gave 0.46 g 492%) of 44 as a dark-red oil. H NMR
After warming to rt and stirring for 1 h, the reaction mixture
was cooled to 2788C and methyl chloroformate 40.97 mL,
12.5 mmol) was added. After stirring for 1 h at rt, the reac-
tion was quenched with NH4Cl 44sat, aq.) 30 mL). The
aqueous phase was extracted with ether 4100£3 mL),
dried 4MgSO4), and concentrated. Flash chromatography
4hexanes/ethyl acetate 5:1) gave 0.87 g 482%) of 43 as a
4500 MHz, CDCl3) d 4ppm) 6.80 4bs, 1H), 6.36 4d, Jˆ
15.6 Hz, 1H), 5.68 4bs, 1H), 3.82 4s, 3H), 2.68 4s, 2H),
1.90 4s, 2H), 1.20 4s, 6H); IR 4CCl4) 2925, 2104, 2073,
2042, 1709, 1234 cm21; HRMS calcd for C18H17O9Co2
4M1H) 494.9537, found 494.9536.
3.1.11. Preparation of [1-methoxy-2-ethyloxycarbonyl-4-
070-ethyloxycarbonyl-50-heptyn-20,20-dimethyl-10-car-
bonyl)-5-oxo-6-methyl-[4.2.1]-9-oxabicyclic-7-nonene]
dicobalt hexacarbonyl complex 045) and 046). A solution
of 1 40.02 g, 0.088 mmol) and DMF 40.4 mL) was added to a
slurry of NaH 40.0026 g, 0.088 mmol) DMF 40.1 mL) at
08C. After stirring for 0.5 h, a solution of [methyl 6,6-
dimethyl-7-oxo-8-nonene-2-ynoate] dicobalt hexacarbonyl
complex 44 40.054 g, 0.11 mmol) and DMF 40.2 mL). The
reaction mixture was quenched with NaHCO3 44sat, aq.)
0.5 mL) after 1 h. The mixture was extracted with ethyl
acetate 43£10 mL), the extracts were dried 4MgSO4), and
concentrated. Flash chromatography 4hexanes/ethyl acetate
3:1) gave 0.02 g 432%) of 45 and 0.012 g 419%) of 46 as red
oils. 45: IR 4CCl4) 2938, 2098, 2067, 2036, 1709,
1
colorless oil. H NMR 4250 MHz, CDCl3): d 4ppm) 5.58
4ddd, Jˆ17.2, 10.4, 8.2 Hz, 1H), 5.21 4dd, Jˆ10.4, 1.9 Hz,
1H), 5.10 4dd, Jˆ17.1, 2.0 Hz, 1H), 4.58 4d, Jˆ6.9 Hz, 1H),
4.38 4d, Jˆ6.9 Hz, 1H), 3.67 4s, 3H), 3.57 4d, Jˆ8.2 Hz,
1H), 3.30 4s, 3H), 2.30 4ddd, Jˆ17.0, 10.4, 6.1 Hz, 1H),
2.21 4ddd, Jˆ17.0, 10.0, 6.1 Hz, 1H), 1.65 4ddd, Jˆ13.6,
10.0, 6.5 Hz, 1H), 1.47 4ddd, Jˆ13.7, 10.8, 6.1 Hz, 1H),
0.84 4s, 3H), 0.82 4s, 3H); 13C NMR 462.5 MHz, CDCl3)
154.0, 134.4, 127.1, 119.6, 93.6, 90.2, 83.6, 72.4, 55.6,
52.3, 36.5, 36.5, 23.0, 13.4; IR 4CCl4) 2963, 2895, 2240,
1721, 1437, 1266 cm21; HRMS calcd for C14H23O4 4M1H)
255.1598, found 255.1596.
3.1.8. Preparation of methyl 6,6-dimethyl-7-hydroxy-8-
nonene-2-ynoate. To a solution of 43 40.82 g, 3.2 mmol)
and MeOH 416 mL) was added six drops of HCl 4conc.).
The reaction mixture was then heated to re¯ux for 3 h. After
cooling to rt, the reaction was quenched with NH4Cl 44sat,
aq.) 15 mL), and extracted with ether 480 mL£3). The
extracts were dried 4MgSO4) and concentrated. Flash
chromatography 4hexanes/ethyl acetate 3:1) gave 0.55 g
482%) of methyl 6,6-dimethyl-7-hydroxy-8-nonene-2-
1227 cm21
; HRMS calcd for C29H31O14 Co24M1H)
721.0378, found 721.0369.46: IR 4CCl4) 2956, 2104,
2067, 2042, 1715, 1234 cm21. HRMS calcd for C29H31O14
Co2 4M1H) 721.0378, found 721.0369.
3.1.12. Preparation of 1-methoxy-2-ethyloxycarbonyl-4-
070-ethyloxycarbonyl-50-heptyn-20,20-dimethyl-10-car-
bonyl)-5-oxo-6-methyl-[4.2.1]-9-oxabicyclic-7-nonene. To
a solution of 45 413 mg, 0.018 mmol) and CH2Cl2 was added
1
ynoate as a colorless oil. H NMR 4600 MHz, CDCl3) d

8036
Q. Xu et al. / Tetrahedron 57 '2001) 8029±8037
TMANO 413 mg, 0.18 mmol). The mixture was concen-
trated after 1 h. Flash chromatography 4hexanes/ethyl
acetate 5:1) gave 5 mg 464%) of 1-methoxy-2-ethyloxy-
carbonyl-4-470-ethyloxycarbonyl-50-heptyn-20,20-dimethyl-
10-carbonyl)-5-oxo-6-methyl-[4.2.1]-9-oxabicyclic-7-nonene
as a colorless oil. 1H NMR 4500 MHz, CDCl3) d 4ppm) 6.13
4d, Jˆ5.8 Hz, 1H), 6.02 4d, Jˆ5.8 Hz, 1H), 4.58 4dd, Jˆ
11.5, 1.5 Hz, 1H), 4.13 4m, 2H), 3.73 4s, 3H), 3.28 4s, 3H),
3.13 4dd, Jˆ13.0, 4.0 Hz, 1H), 2.33 4ddd, Jˆ17.0, 10.0,
5.5 Hz, 1H), 2.27 4ddd, Jˆ17.0, 10.0, 5.5 Hz, 1H), 2.04
4ddd, Jˆ15.5, 12.5, 12.5 Hz, 1H), 1.95 4ddd, Jˆ14.0,
10.0, 6.0 Hz, 1H), 1.82 4ddd, Jˆ13.5, 3.5, 1.5 Hz, 1H),
1.63 4ddd, Jˆ14.0, 10.5, 6.0 Hz, 1H), 1.54 4s, 3H), 1.25 4t,
Jˆ 7.1 Hz, 3H), 1.11 4s, 3H), 1.05 4s, 3H). 13C NMR
4125 MHz, CDCl3) 211.8, 209.2, 171.1, 154.2, 136.3,
129.6, 116.8, 91.9, 89.6, 72.8, 61.0, 56.3, 55.1, 52.5, 51.0,
47.8, 36.6, 28.6, 24.8, 22.5, 21.0, 14.3, 14.1; HRMS calcd
for C23H31O8 4M1H) 435.2019, found 435.2018.
4CCl4) 2938, 1789, 1734, 1672, 1073 cm21; HRMS calcd
for C25H33O9 4M1H) 477.2125, found 477.2132.
3.1.15. Preparation of 50 and 47 from the coupling of 1
with 39. A solution of 1 422 mg, 0.097 mmol) and DMF
40.4 mL) was added to
a slurry of KH 43.9 mg,
0.097 mmol) and DMF 40.4 mL) at0 8C. After 0.5 h, a solu-
tion of 39 422 mg, 0.107 mmol) and DMF 40.5 mL) was
added over 1 h. The resulting mixture was warmed to rt
and stirred for an additional 0.5 h. To the mixture was
added DMAP 411.8 mg, 0.097 mmol) and Ac2O 40.02 mL,
0.2 mmol). After 0.5 h, the reaction was poured into phos-
phate buffer 4pH 7.5). The aqueous phase was extracted with
CH2Cl2, dried 4Na2SO4), and concentrated. Flash chroma-
tography 4hexanes/ethyl acetate 2:1) gave 10 mg 422%) of
47 and 9 mg 420%) of enol acetate 50 as colorless oils. 47
4mixture of diastereomers): major isomer: 1H NMR
4600 MHz, CD2Cl2) d 4ppm) 6.22 4d, Jˆ5.8 Hz, 1H), 6.16
4d, Jˆ5.8 Hz, 1H), 5.79 4s, 1H), 4.17±4.10 4m, 2H), 3.73±
3.70 4m,1H?), 3.69 4s, 3H), 3.29 4s, 3H), 3.20 4dd, Jˆ13.1,
2.8 Hz, 1H), 2.65 4ddt, Jˆ17.8, 6.7, 2.2 Hz, 1H), 2.39 4dd,
Jˆ15.3, 13.1 Hz, 1H), 1.75 4?), 1.48 4s, 3H), 1.25 4t, Jˆ
7.2 Hz, 3H), 1.14 4s, 3H), 1.07 4s, 3H); 13C NMR 4125
MHz, CDCl3) d 4ppm) 214.3, 209.0, 171.0, 166.3, 157.9,
135.4, 130.7, 120.2, 117.5, 92.4, 74.4, 61.0, 51.9, 51.3, 51.2,
44.4, 34.0, 32.5, 26.1, 24.2, 22.5, 21.1, 14.1; IR 4CCl4) 2987,
2944, 1734, 1709, 1178 cm21; HRMS calcd for C23H30O8
4M1H) 435.2019, found 435.2027.
3.1.13. Preparation of 1-methoxy-2-ethyloxycarbonyl-4-
070-ethyloxycarbonyl-50-heptyn-20,20-dimethyl-10-car-
bonyl)-5-oxo-6-methyl-[4.2.1]-9-oxabicyclic-7-nonene
048). To a solution of 46 49 mg, 0.0125 mmol) and CH2Cl2
was added TMANO 49 mg, 0.125 mmol). After 1 h the
reaction mixture was concentrated. Flash chromatography
4hexanes/ethyl acetate 2:1) gave 3.5 mg 465%) of 48 as a
colorless oil. 1H NMR 4250 MHz, CDCl3) d 4ppm) 6.08 4d,
Jˆ5.7 Hz, 1H), 5.74 4d, Jˆ5.7 Hz, 1H), 5.72 4dd, Jˆ11.2,
1.9 Hz, 1H), 4.29±4.10 4m, 2H), 3.72 4s, 3H), 3.29 4s, 3H),
2.99 4dd, Jˆ4.7, 2.2 Hz, 1H), 2.26 4ddd, Jˆ9.4, 6.7, 2.7 Hz,
2H), 2.05 4ddd, Jˆ15.9, 11.2, 4.8 Hz, 1H), 1.97 4ddd, Jˆ
13.9, 9.3, 6.7 Hz, 1H), 1.76 4dt, Jˆ15.9, 2.2 Hz, 1H), 1.63
4partially obscured ddd, Jˆ13.6, 9.8, 6.2 Hz, 1H), 1.54
4s, 3H), 1.27 4t, Jˆ7.1 Hz, 3H), 1.11 4s, 3H), 1.06 4s, 3H);
13C NMR 462.5 MHz, CDCl3) d 4ppm) 213.0, 210.1,
171.8, 155.0, 137.4, 130.1, 116.2, 92.8, 89.8, 73.0, 60.9,
53.0, 52.5, 51.2, 49.0, 48.0, 36.5, 28.0, 24.6, 22.3, 21.0,
1
Minor isomer: H NMR 4600 MHz, CDCl3): d 4ppm) 6.14
4d, Jˆ5.8 Hz, 1H), 6.04 4d, Jˆ5.8 Hz, 1H), 5.52 4s, 1H),
4.13 4m, 2H), 3.68 4s, 3H), 3.35 4m, 1H), 3.27 4s, 3H),
2.88 4m, 1H), 2.33±2.30 4m, 2H), 2.25 4dd, Jˆ15.0,
4.2 Hz, 1H), 1.92 4dd, Jˆ15.0, 12.6 Hz, 1H), 1.67 4dd, Jˆ
6.6, 4.8 Hz, 1H), 1.45 4s, 3H), 1.27 4t, Jˆ7.2 Hz, 3H), 1.16
4s, 3H), 1.12 4s, 3H).
14.4, 14.2; IR 4CCl4) 2963, 2240, 1728, 1264 cm21
;
HRMS calcd for C23H31O8 4M1H) 435.2019, found
435.2018.
Acknowledgements
We are grateful to the NSF 4CAREER AWARD to JDR) for
support of this research. The authors would also like to
thank Dr Neil Jacobsen and Dr Arpad Somagyi for help
with NMR and mass spectra experiments, respectively.
3.1.14. Preparation of acetate 050). A solution of 1-meth-
oxy-2-ethyloxycarbonyl-4-470-ethyloxycarbonyl-50-heptyn-
20,20-dimethyl-10-carbonyl)-5-oxo-6-methyl-[4.2.1]-9-oxa-
bicyclic-7-nonene 416 mg, 0.037 mmol) and DMF 41.2 mL)
was added to a slurry of KH 44.4 mg, 0.11 mmol) and DMF
40.3 mL) at0 8C. The reaction mixture was immediately
warmed to rt. After 1 h, DMAP 44.5 mg, 0.037 mmol) and
Ac2O 411 mg, 0.074 mmol) were added. After another 1 h,
the reaction mixture was poured into phosphate buffer 4pH
7.5). The aqueous phase was extracted with CH2Cl2, t he
extracts were dried 4Na2SO4), and concentrated. Flash
chromatography 4hexanes/ethyl acetate 2:1) gave 8.5 mg
References
1. 4a) Nicolaou, K. C.; van Delft, F. L.; Ohshima, T.;
Vourloumis, D.; Xu, J.; Hosokawa, S.; Pfefferdorn, J.; Kim,
S.; Li, T. Angew. Chem., Int. Ed. 1997, 36, 2520. 4b) Nicolaou,
K. C.; Xu, J. Y.; Kim, S. J. Am. Chem. Soc. 1998, 120, 8674.
4c) Chen, X. T.; Zhou, B. S.; Bhattacharya, S. K.; Gutteridge,
C. E.; Pettus, T. R. R.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 1998, 37, 789. 4d) Chen, X. T.; Bhattacharya, S. K.; Zhou,
B. S.; Gutteridge, C. E.; Pettus, T. R. R.; Danishefsky, S. J.
J. Am. Chem. Soc. 1999, 121, 6563.
1
450%) of enol acetate 50 as a red oil. H NMR 4500 MHz,
CDCl3) d 4ppm) 6.28 4d, Jˆ6.0 Hz, 1H), 5.96 4d, Jˆ6.0 Hz,
1H), 4.20 4q, Jˆ7.0 Hz, 2H), 3.67 4s, 3H), 3.13 4s, 3H), 2.90
4dd, Jˆ11.3, 1.2 Hz, 1H), 2.71 4dd, Jˆ13.5, 1.5 Hz, 1H),
2.43±2.39 4m, 2H), 2.29 4s, 3H), 2.27 4dd, Jˆ13.5, 11.5 Hz,
1H), 1.91±1.88 4m, 2H), 1.57 4s, 3H), 1.31 4t, Jˆ7.1 Hz,
3H), 1.19 4s, 3H), 1.14 4s, 3H); 13C NMR 4125 MHz, CDCl3)
d 4ppm) 202.6, 172.8, 167.9, 164.8, 155.5, 147.3, 135.8,
135.4, 127.9, 118.7, 118.1, 90.5, 60.7, 52.3, 50.4, 50.3,
40.7, 35.8, 28.8, 27.1, 24.2, 24.1, 23.5, 21.3, 14.2; IR
2. Nicolaou, K. C.; Ohshima, T.; Hosokawa, S.; van Delft, F. L.;
Vourloumis, D.; Xu, J. Y.; Pfefferkorn, J.; Kim, S. J. Am.
Chem. Soc. 1998, 120, 8674.
3. 4a) Nicolaou, K. C.; Xu, J.-Y.; Kim, S.; Ohshima, T.;
Hosokawa, S.; Pfefferdorn, J. J. Am. Chem. Soc. 1997, 119,
11353. 4b) Nicolaou, K. C.; Xu, J.; Kim, S.; Pfefferkorn, J.;

Q. Xu et al. / Tetrahedron 57 '2001) 8029±8037
8037
Ohshima, T.; Vourloumis, D.; Hosokawa, S. J. Am. Chem.
Soc. 1998, 120, 8661.
14. The corresponding carbon and nitrogen bridged bicyclo-
[2.2.1]heptenones analogous to 14 also give mixtures of ole®n
isomers 4see Ref. 7a and Weerasekare, M.; Rainier, J. D.,
unpublished results).
4. MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 1995,
117, 10391. Overman, L. E.; Pennington, L. D. Org. Lett.
2000, 2, 2683.
15. See: Chenna, A.; Donnelly, J.; McCullough, K. J.; Proctor,
G. R.; Redpath, J. J. Chem. Soc., Perkin Trans. 1 1990, 261
and references cited therein. For the analogous ring expansion
of b-ketophophonates see: Ruder, S. Z.; Kulkarni J. Org.
Chem. 1995, 60, 3084.
5. 4a) See Ref. 4b 4b) Paquette, L. A.; Moradei, O. M.;
Bernardelli, P.; Lange, T. Org. Lett. 2000, 2, 1875. 4c) Gallou,
F.; MacMillan, D. W. C.; Overman, L. E.; Paquette, L. A.;
Pennington, L. D.; Yang, J. Org. Lett. 2001, 3, 135.
6. 4a) By, K.; Kelly, P. A.; Kurth, M. J. Tetrahedron 2001, 57,
1183. 4b) Carter, R.; Hodgetts, K.; McKenna, J. Tetrahedron
2000, 56, 4367. 4c) Jung, M. E.; Huang, A.; Johnson, T. W.
Org. Lett. 2000, 2, 1835. 4d) Baron, A.; Caprio, V.; Mann, J.
Tetrahedron Lett. 1999, 40, 9321. 4e) Ceccarelli, S.; Piarulli,
U.; Gennari, C. Tetrahedron Lett. 1999, 40, 153.
16. Spreitzer, H.; Pichler, A.; Holzer, W.; Toth, I.; Zuchart, B.
Helv. Chim. Acta 1997, 80, 139.
17. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
18. It is also possible to envision a `round trip' mechanistic path-
way for the conversion of 1!40 where the anion from the
initial Michael addition of 1 and 39 undergoes a 6-exo-dig
cyclization onto the pendant alkyne. Anionic cyclization
onto the pendant ketone and oxyanionic fragmentation of
the bicyclic ring system would give 40.
7. For preliminary communications describing portions of the
investigations described here see: 4a) Rainier, J. D.; Xu, Q.
Org. Lett. 1999, 1, 1161. 4b) Rainier, J. D.; Xu, Q. Org. Lett.
1999, 1, 27.
19. Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L.
J. Am. Chem. Soc. 1997, 119, 4353.
8. We were most intrigued by the Dowd cyclization, fragmen-
tation protocol. To the best of our knowledge, this has not been
demonstrated in bicyclic ring systems. See: 4a) Dowd, P.;
Choi, S.-C. Tetrahedron 1989, 45, 77. 4b) Wang, C.; Gu, X.;
Yu, M. S.; Curran, D. P. Tetrahedron 1998, 54, 8355.
9. For reviews that discuss fragmentation reactions, see: Ref. 12
and 4a) Mehta, G.; Singh, V. Chem. Rev. 1999, 99, 881.
4b) Roxburgh, C. J. Tetrahedron 1993, 49, 10749.
4c) Weyerstahl, P.; Marschall Comprehensive Organic
Synthesis; Trost, B. M., Ed.; ;1991; Vol. 5, p. 1041.
10. Leroy, J. Tetrahedron Lett. 1992, 33, 2969.
20. Schreiber, S. L.; Sammakia, T.; Crowe, W. E. J. Am. Chem.
Soc. 1986, 108, 3128.
21. We have not been able to determine the relative stereo-
chemistry of the spiro unit in 47. The gross structure of 47
was determined by the similarities of its spectra to the spiro
fused compound obtained from the attempted ring expansion
reaction of a bis-activated diene analogous to 39. The structure
of this compound was determined using x-ray crystallography
4Rainier, J. D.; Xu, Q., unpublished results).
22. We do not have a good explanation for the lack of 47 under
these reaction conditions.
11. Leroy isolated 13 in 68±83% yield from the hydrolysis of the
corresponding dimethyl acetal using Na®on-H 4see Ref. 10).
12. For an excellent review covering the chemistry of oxabicyclo-
[2.2.1]heptanes see: Vogel, P.; Cossy, J.; Plumet, J.; Arjona,
O. Tetrahedron 1999, 55, 13521.
23. Ring expanded product 40 was unstable to chromatography.
Enol acetate 50 was much more stable.
24. Attempts to carry out the ring expansion using the correspond-
ing bis-activated diene resulted in the formation of the spiro
compound analogous to 47.
13. The ole®n geometry was established by derivatizing 17 and 18
and then by carrying out the appropriate NOE experiments.
See Ref. 7a.
25. When NaH was used as the base, we isolated 40 in 10% yield.